The HIV-1 (Human Immunodeficiency Virus) is a member of the retroviral family which contains a single- stranded RNA genome and is the major etiological agent involved in the development of acquired immunodeficiency syndrome or AIDS. The World Health Organization now estimates that in 2016 over 40 million people worldwide are infected. The most recent CDC report estimates that in the US over 1.2 million people are infected including about 13% who are unaware of their infections. With the development of antiretroviral therapy (ART), there has been much needed progress over the past decade. The continual emergence of drug resistance HIV variants and side effects of life long therapy necessitates the development of new therapies.. Developing combination therapies that might also be effective would also be very beneficial. There are a number of potential targets in the life cycle of the HIV virus including HIV reverse transcriptase (RT), HIV protease, and more recently viral entry, attachment, and integration. Drugs targeting RT remain a cornerstone of AIDS therapy in most therapeutic regimens. The drugs that target HIV-1 RT are divided into two classes: nucleoside inhibitors (NRTIs) and non-nucleoside inhibitors (NNRTIs). The rapid development of drug resistance by the error prone RT, side effects, and issues of viral vs host polymerase selectivity necessitate the discovery of more effective NRTIs and NNRTIs with improved safety, pharmacological, and drug resistance profiles. Building on the discovery of a very potent novel lead compound, using computationally, mechanism, and structure-guided design, the PI and an established set of collaborators, have used lead optimization to develop three new classes of novel NNRTIs. These new NNRTIs have excellent potency on WT and drug resistant strains of HIV, optimal pharmacological properties, synergy with clinically relevant NRTIs, and efficacy in AIDS hu-mouse models. Comprehensive studies are described to develop these compounds into preclinical candidates that might also be useful in combination therapy.